The present invention relates to new homogeneous ferrocenyldiphosphine-ruthenium complexes, good catalysts for the hydrogenation of d-thiophene to d-thiophane, and to a new process for the hydrogenation of d-thiophene 3 to d-thiophane 4 using ferrocenyldiphosphine-ruthenium complexes as catalysts.
D-Biotin is one of the water-soluble B vitamins. It plays an essential role as a coenzyme in carboxylation reactions related to biochemical processes such as gluconeogenesis and fatty acid biosynthesis.
D-Biotin deficiency in poultry and swine causes a series of severe symptoms. These deficiencies are corrected by feeding Biotin as a feed additive. Hence, it is commercial importance.
Goldberg and Stembach""s synthetic scheme, improved later by Gerecke etal, is regarded to be still one of the most efficient processes for the commercial production of natural-form D-Biotin. [U.S. Pat. No. 2,489,232, U.S. Pat. No. 2,489,235; U.S. Pat. No. 2,489,238; Helv. Chim. Acta, vol.53, 991(1970)].
The present invention relates to new homogeneous ferrocenyldiphosphine-ruthenium complexes, good catalysts for the hydrogenation of d-thiophene to d-thiophane, and to a new process for the hydrogenation of d-thiophene of the formula 3 to d-thiophane of the formula 4 using ferrocenyldiphosphine-ruthenium complexes as catalysts. 
in which R signifies xe2x80x94OCH3(3a), xe2x80x94OCH2CH3(3b), xe2x80x94CH2COOH(3c), xe2x80x94CH2COOCH3(3d) or xe2x80x94CH2COOEt(3e) and Bz signifies benzyl group.
d-Thiophene of the formular 3, which is derived from the reaction of d-Thiophene of the formula 2 with appropriate Grignard or Wittig reagents, is the intermediate of D-Biotin synthesis. 
Up to present time, the conversion of d-Thiophene of the formula 3 to d-Thiophene of the formula 4 with the desired all-cis configuration at centers C-2, C-3, and C-4(see atom numbering on D-Biotin structure of the formula 1) is known to be accomplished by the catalytic hydrogenation using Palladium on carbon, Palladium hydroxide on carbon or Nickel catalyst, the heterogeneous catalysts.
However, many disadvantage are experienced with the uses of the heterogeneous catalysts. Palladium on carbon (dry form) is very expensive, air-sensitive and susceptible to sulfur poison. Palladium hydroxide on carbon is also expensive and sensitive to air. Nickel catalyst is less expensive but requires high pressure and high temperature for the hydrogenation of exocyclic double bond, which may not be adequate for the commercial application.
We found out new homogeneous catalysts for the hydrogenation of exocyclic double bond transforming d-thiophene of the formular 3 to d-thiophane of the formula 4, exhibiting the desired all-cis configuration at C-2, C-3 and C-4 centers. The homogeneous catalysts, we want to report herein, are new Ferrocenyldiphosphine-ruthenium complexes such as 1,1xe2x80x2-Bis(diphenylphosphino)-ferrocene-ruthenium complex, which compensate all disadvantages inheriting from the uses of known heterogeneous catalysts.
The above-mentioned new homogeneous catalysts which we invented are less expensive, less sensitive to air, easy to handle less susceptible to sulfur poison, and do not require high pressure and high temperature.
Accordingly, the object of the present invention is to provide new homogeneous ferrocenyldiphosphine-ruthenium complexes which compensate all disadvantages of the known heterogeneous catalysts and which can replace existing heterogeneous catalysts such as Palladium and Nickel catalysts for the hydrogenation of exocyclic double bond of the d-thiophene of the formula 3. 
in which R signifies xe2x80x94OCH3(3a), xe2x80x94OCH2CH3(3b), xe2x80x94CH2COOH(3c), xe2x80x94CH2COOCH3(3d) or xe2x80x94CH2COOEt(3e) and Bz signifies benzyl group.
Other object of the present invention is to provide a new method which utilizes the homogeneous catalysts for the hydrogenation of exocyclic double bond transforming d-thiophene of the formula 3 to d-thiophane of the formula 4, exhibiting the desired all-cis configuration at C-2, C-3 and C-4 centers.
The object of the present invention is achieved by providing a Ferrocenyldiphosphine-ruthenium complex selected from the group consisting of the complexes whose formulas are described as follow:
RuCl2(COD)n+PP in situ,xe2x80x83xe2x80x831.
[RuCl2(PP)]2(NEt3), andxe2x80x83xe2x80x832.
RuHCl(PP)2xe2x80x83xe2x80x833.
wherein
COD signifies cyclooctadiene of the following formula, 
and PP signifies a diphosphine ligand of the general formula 
in which R is C1-C12 alkyl, C5-C12 cycloalkyl, C1-C4 alkyl or C1-C4 alkoxy-substituted, C5-C12 cycloalkyl, phenyl or phenyl which is substituted by 1 to 3 identical or different members selected from the group consisting of C1-C4, alkyl, C1-C4 alkoxy or halogen;
n is an integral number of 1-3 and the complexes of n=1, n=2 or n=3 exist together with one another.
In an economical view point, the most efficient catalyst, among all tested complexes, is {[1,1xe2x80x2-Bis(diphenylphosphino)ferrocene]dichlororuthenium(II)}2 (triethylamine)[RuCl2(BPPF)]2(NEt3)] complex whose ligand is known and can be prepared as described in J. J. Bishop etal, J. Organometal Chem. 1971, 27, 241.
Examples of suitable solvents of the reaction are aromatic hydrocarbons such as benzene or toluene, ethers such as diethyl ether, tetrahydrofuran or dioxane, chlorinated hydrocarbons such as dichloromethane or dichloroethane, alcohols such as methanol, ethanol or isopropyl alcohol, esters such as ethyl acetate or butyl acetate and mixtures of these solvents with one another. Preference is given to using methanol.
The addition of small amount of toluene to the substrate increases the hydrogenation rate, of which the amounts range from 1% to 50%, preferably 10%. However, the presence of water exhibits the opposite effect. The content of up to 0.1% water does not deteriorate the hydrogenation rate.
The hydrogenation is carried out at a temperature of from 20xc2x0 C. to 150xc2x0 C., preferably at 20xc2x0 C. to 100xc2x0 C., and at a pressure of from 1 kg/cm2 to 200 kg/cm2, preferably 10 to 30 kg/cm2. The reaction time is 5 hours to 3 days, preferably 12-24 hours.
The comparative results of the hydrogenation of d-Thiophene 3 to d-Thiophane 4, with various Ferrocenyldiphophine-ruthenium complexes are shown in Table 1.
The Ferrocenyldiphosphine-ruthenium complex prepared in situ gives only the yield of 50%, however, the isolated complex, [RuCl2(BPPF)2(NEt3)], (Entry 1) improves the yield to 85.1%. When the reaction conditions are optimized further, the yields are increased even higher, as shown in Table 2.
Analyses of the yield of 4a in the catalytic hydrogenation are conducted with the following instrument.
High-Performance Liquid Chromatography: SHIMADZU SCL-10A
Column: KROMASLI C8 
Solvent: Acetonitrile/Water(1:1 by volume) at a flow rate 1.5 ml/min.